The integrin type αVβ3 is a receptor for vitronectin [Hermann, P. et al. “The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23” [The Journal of cell biology 144 (1999): 767-75]. It consists of two components, integrin alpha V and integrin beta 3 (CD61), and is expressed by platelets as well as other cell types. It has been shown that inhibitors of αVβ3 like etaracizumab may be used as antiangiogenics.
RNA interference is a well-known process in which the translation of messenger RNA (mRNA) into protein is interfered with by the association or binding of complementary or partially complementary oligonucleotides such as small interfering RNA (siRNA), short hairpin RNA(shRNA), micro RNA (miRNA), or antisense oligonucleotides. siRNAs are doublestranded RNA molecules, usually ranging from 19-25 nucleotides in length that associate with a set of proteins in the cytoplasm known as RISC (RNA-induced silencing complex). RISC ultimately separates the double stranded siRNA allowing one strand to bind or associate with a complementary or partially complementary portion of an mRNA molecule after which the mRNA is destroyed by RISC or otherwise prevented from being translated—consequently suppressing the expression of the encoded protein or gene product.
One of the problems in using nucleic acids such as siRNA in therapeutic applications (especially for systemic administration in humans) has been in delivering the nucleic acids to: (1) particular target tissues or cell types and (2) to the cytoplasm of those cells (i.e., where the mRNA is present and translated into protein). Part of the delivery problem is based on the fact that nucleic acids are negatively charged and easily degraded (especially if unmodified), efficiently filtered by the kidney, and cannot be easily transported to the cytoplasm of the cells by themselves. Thus, a significant amount of research has focused on solving the delivery problem with various carriers and formulations including liposomes, micelles, peptides, polymers, conjugates and aptamers. See Ling et al, Advances in Systemic siRNA Delivery, Drugs Future 34(9): 721 (September 2009). Some of the more promising delivery vehicles have involved the use of lipidic systems including lipid nanoparticles. See Wu et al., Lipidic Systems for In Vivo siRNA Delivery, AAPS J. 11(4): 639-652 (December 2009); International Patent Application Publication No. WO 2010/042877 by Hope et al (“Improved Amino Lipids And Methods For the Delivery of Nucleic Acids”). However, a need remains for further improved targeting of siRNA; as well as substances such as small molecules, peptides, other nucleic acids, fluorescent moieties, and polymers to particular target cells and to the cytoplasm of such cells.